Bioinspired polyene cyclization promoted by intermolecular chiral acetal-SnCl4 or chiral N-acetal-TiCl4: Investigation of the mechanism and identification of the key intermediates

Article abstract of DOI:10.1021/ja802896n

New strategies using chiral acetal or chiral mixed-acetal in the presence of Lewis acids (SnCl₄ or TiCl₄) to promote polyene cyclization reaction are described. Acetal-promoted and mixed-acetal-promoted polyene cyclization products a

Full text of DOI:10.1021/ja802896n

Published on Web 07/08/2008
Bioinspired Polyene Cyclization Promoted by Intermolecular
Chiral Acetal-SnCl4 or Chiral N-Acetal-TiCl4: Investigation of
the Mechanism and Identification of the Key Intermediates
Yu-Jun Zhao and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological UniVersity, Singapore 637371
Received April 19, 2008; E-mail: teckpeng@ntu.edu.sg
Abstract: New strategies using chiral acetal or chiral mixed-acetal in the presence of Lewis acids (SnCl4
or TiCl4) to promote polyene cyclization reaction are described. Acetal-promoted and mixed-acetal-promoted
polyene cyclization products are very versatile and can easily be converted into various optically active
tricyclic and tetracyclic terpenoids. One of the derivatives of the cyclization products was obtained up to
96% ee after a single recrystallization. In addition, an oxocarbenium intermediate was found to be responsible
for the good asymmetric selectivity for this type of reaction.
Scheme 1
Introduction
Although the fundamental works of biomimetic polyene
cyclization have been established as early as the 1960s by Stork
and Eschenmoser,1 this state of the art reaction is still inspiring
the passion and creativity of modern chemists. The key to a
successful polyene cyclization is to have good initiators.
Johnson,2,3 van Tamelene,4 Corey,5 Overman,6 Nishizawa,7 and
others8 have contributed tremendously to the vast development
(1) (a) Stork, G.; Burgstahler, A. W. J. Am. Chem. Soc. 1955, 77, 5068–
5077. (b) Eschenmoser, A.; Ruzika, L.; Jeger, O.; Arigoni, D. HelV.
Chim. Acta 1955, 38, 1890–1904. For an English translation and
historical perspective on the 50th Anniversary of the Eschenmoser,
Ruzika, Jeger, and Arigoni 1955 paper, see: (c) Eschenmoser, A.;
Arigoni, D. HelV. Chim. Acta 2005, 88, 3011–3050.
of 20th century’s cationic polyene cyclization chemistry using
different initiators (Scheme 1). These initiators include acetal,
allylic alcohol, epoxide, Hg(II), etc., which have been success-
fully applied to the syntheses of many complex molecules.
Shortly after Johnson’s acetal protocol, Speckamp9 reported
the first intramolecular N-acetal-promoted polyene cyclization.
The acyl iminium was the active species that is responsible for
the initiation of this cyclization. In addition, transition metals
such as Pt(II) and Pd(II)10 have also been developed as practical
initiators for this type of cationic transformation.
(2) (a) Johnson, W. S.; Kinnel, R. B. J. Am. Chem. Soc. 1966, 88, 3861–
3862. (b) Johnson, W. S.; Jensen, N. P.; Hooz, J. J. Am. Chem. Soc.
1966, 88, 3859–3860.
(3) For reviews of Johnson’s work, see: (a) Johnson, W. S. Tetrahedron
1991, 47, xi–1. (b) Johnson, W. S. Angew. Chem., Int. Ed. Engl. 1976,
15, 9–16. (c) Johnson, W. S. Acc. Chem. Res. 1968, 1, 1–8.
(4) (a) van Tamelen, E. E.; Willet, J.; Schwartz, W.; Nadeau, R. J. Am.
Chem. Soc. 1966, 88, 5937. (b) van Tamelen, E. E.; James, D. R.
J. Am. Chem. Soc. 1977, 99, 950–951. (c) van Tamelen, E. E. Acc.
Chem. Res. 1975, 8, 152–158. (d) van Tamelen, E. E.; Hwu, J. R.
J. Am. Chem. Soc. 1983, 105, 2490–2491.
(5) (a) Corey, E. J.; Tius, M. A.; Das, J. J. Am. Chem. Soc. 1980, 102,
1742–1744. (b) Corey, E. J.; Reid, J. G.; Myers, A. G.; Hahl, R. W.
J. Am. Chem. Soc. 1987, 109, 918–919. (c) Corey, E. J.; Lee, J. J. Am.
Chem. Soc. 1993, 115, 8873–8874. (d) Corey, E. J.; Wood, H. B., Jr.
J. Am. Chem. Soc. 1996, 118, 11982–11983. (e) Corey, E. J.; Staas,
D. D. J. Am. Chem. Soc. 1998, 120, 3526–3527. (f) Huang, A. X.;
Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 9999–10003.
(6) Bogensta¨tter, M.; Limberg, A.; Overman, L. E.; Tomasi, A. L. J. Am.
Chem. Soc. 1999, 121, 12206–12207.
Another important initiator is proton, which was recognized
as good initiator for polyene cyclization by Stork and
Eschenmoser. However, the asymmetric version was only
(9) (a) Hiemstra, H.; Speckamp, W. N. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 2,
Chapter 4.5, p 1047. (b) Dijkink, J.;; Speckamp, W. N. Tetrahedron
Lett. 1977, 935–938. (c) Dijkink, J.; Speckamp, W. N. Tetrahedron
1978, 34, 173–178.
(7) (a) Nishizawa, M.; Takenaka, H.; Nishide, H.; Hayashi, Y. Tetrahedron
Lett. 1983, 24, 2581. (b) Nishizawa, M.; Takenaka, H.; Hayashi, Y.
J. Am. Chem. Soc. 1985, 107, 552–523. (c) Nishizawa, M.; Takenaka,
H.; Hayashi, Y. J. Org. Chem. 1986, 51, 806–813.
(10) (a) Feducia, J. A.; Gagne´, M. R. J. Am. Chem. Soc. 2008, 130, 592–
599. (b) Mullen, C. A.; Gagne´, M. R. J. Am. Chem. Soc. 2007, 129,
11880–11881. (c) Hegedus, L. S. In ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: Elmsford, NY, 1991; Vol. 4, p
551. (d) Hegedus, L. S. In Transition Metals in the Synthesis of
Complex Organic Molecules; University Science Books: Mill Valley,
CA, 1994; p 199.
(8) For recent reviews on biomimetic polyene cyclization, see: (a)
Sutherland, J. K. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 5, Chapter 1.9, p 341. (b)
Bartlett, P. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
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J. N. Chem. ReV. 2005, 105, 4730–4756.
9
10024 J. AM. CHEM. SOC. 2008, 130, 10024–10029
10.1021/ja802896n CCC: $40.75
2008 American Chemical Society

Bioinspired Polyene Cyclization
A R T I C L E S
Scheme 2
Scheme 6
Scheme 3
Later, several carbo-radical-initiated polyene cyclization
reactions were reported. Snider,14 Demuth,15 Pattenden,16 and
Yang17 developed three new protocols, namely, using 1,3-
dicarbonyl radical, photochemically generated radical, and acyl
radical as initiators. Very recently, radical generated from
reductively opening of epoxide was also successfully used as
initiator for polyene cyclization by Oltra.18
Although many successes had been accomplished, biomimetic
cationic polyene cyclizations with high asymmetric selectivities
and high efficiency are still challenging problems in both
academia and industries.19 To tackle this problem, we reported
an asymmetric acetal-initiated intermolecular polyene cyclization
(Scheme 3).20
Scheme 4
In this paper, we investigated the reaction using N-acetals
(Scheme 4). One of the derivatives of the cyclization products
was obtained in moderate yield with up to 96% ee after a single
recrystallization. In addition, an oxocarbenium intermediate was
found to be responsible for the good asymmetric selectivity for
this type of reaction.
Scheme 5. Functionalization of Acetal-Initiated Cyclization
Products to Various Terpenoids
Results
Treatment of polyene 1 with chiral acetal A in the presence
of SnCl4 afforded the tricyclic product 2 in 89% yield with
(14) (a) Snider, B. B.; Mohan, R.; Kates, S. A. J. Org. Chem. 1985, 50,
3659. (b) Dombroski, M. A.; Kates, S. A.; Snider, B. B. J. Am. Chem.
Soc. 1990, 112, 2759. (c) Zhang, Q.-W.; Mohan, R. M.; Cook, L.;
Kazanis, S.; Peisach, D.; Foxman, B. M.; Snider, B. B. J. Org. Chem.
1993, 58, 7640. (d) Zoretic, P. A.; Zhang, Y. Z. Tetrahedron Lett.
1996, 37, 1751–1754. For a review, see: (e) Snider, B. B. Chem. ReV.
1996, 96, 339–363.
(15) (a) Heinemann, C.; Demuth, M. J. Am. Chem. Soc. 1999, 121, 4894–
4895. (b) Demuth, M.; Hoffmann, U.; Gao, Y. M.; Pandey, B.; Klinge,
S.; Warzecha, K. D.; Kru¨ger, C.; Roth, H. D. J. Am. Chem. Soc. 1993,
115, 10358–10359. (c) Xing, X.-C.; Demuth, M. Eur. J. Org. Chem.
2001, 3, 537–544. (d) Rosales, V.; Zambrano, J.; Demuth, M. Eur. J.
Org. Chem. 2004, 6, 1798–1802.
established recently by Yamamoto11 who demonstrated that
chiral LBA catalysts could be used to construct multiple rings
with high enantioselectivities. In addition, Ishihara has also
elegantly established a highly enantioselective polyene cy-
clization reaction promoted by chiral electrophilic halogen
atom.12
(16) (a) Pattenden, G.; Gonzalez, M. A.; McCulloch, S.; Walter, A.;
Woodhead, S. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12024–
12029. (b) Boehm, H. M.; Handa, S.; Pattenden, G.; Roberts, L.; Blake,
J. A.; Li, W. S. J. Chem. Soc., Perkin Trans. 1 2000, 3522–3538. (c)
Pattenden, G.; Roberts, L.; Blake, J. A. J. Chem. Soc., Perkin Trans.
1 1998, 863–868. (d) Chen, L.-G.; Gill, B.; Pattenden, G. Tetrahedron
Lett. 1994, 35, 2593–2596.
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Yang, D.; Xu, M.; Bian, M. Y. Org. Lett. 2001, 3, 111–114. (c) Yang,
D.; Ye, X. Y.; Gu, S.; Xu, M. J. Am. Chem. Soc. 1999, 121, 5579–
5580.
In addition to cationic polyene cyclization, Breslow13 in 1968
demonstrated that oxygen radical was also a promising initiator
for polyene cyclization (Scheme 2).
(18) (a) Justicia, J.; Oller-Lopez, J. L.; Campan˜a, A. G.; Oltra, J. E.; Cuerva,
J. M.; Bun˜uel, E.; Cardenas, D. J. J. Am. Chem. Soc. 2005, 127, 14911–
14921. (b) Justicia, J.; Oltra, J. E.; Barrero, A. F.; Guadan˜o, A.;
Gonza´lez-Coloma, A.; Cuerva, J. M. Eur. J. Org. Chem. 2005, 712–
718. (c) Justicia, J.; Oltra, J. E.; Cuerva, J. M. J. Org. Chem. 2004,
64, 5803–5806. (d) Barrero, A. F.; Cuerva, J. M.; Herrador, M. M.;
Valdibia, M. V. J. Org. Chem. 2001, 66, 4074–4078.
(11) (a) Ishihara, K.; Ishibashi, H.; Yamamoto, H. J. Am. Chem. Soc. 2001,
123, 1505–1506. (b) Ishihara, K.; Ishibashi, H.; Yamamoto, H. J. Am.
Chem. Soc. 2002, 124, 3647–3655. (c) Uyanik, M.; Ishihara, K.;
Yamamoto, H. Org. Lett. 2006, 8, 5649–5652. (d) Yamamoto, H.;
Ishihara, K.; Ishibashi, H. J. Am. Chem. Soc. 2004, 126, 11122–11123.
(e) Uyanik, M.; Ishibashi, H.; Ishihara, K.; Yamamoto, H. Org. Lett.
2005, 7, 1601–1604. (g) Nakamura, S.; Ishihara, K.; Yamamoto, H.
J. Am. Chem. Soc. 2000, 122, 8131–8140. (h) Ishihara, K.; Nakamura,
S.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 4906–4907.
(12) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900–903.
(13) (a) Breslow, R.; Barrett, E.; Mohaosi, E. Tetrahedron Lett. 1962, 3,
1207–1211. (b) Breslow, R.; Olin, S. S.; Groves, J. T. Tetrahedron
Lett. 1968, 9, 1837–1840.
(19) (a) Peterson, E. A.; Overman, L. E. Proc Natl. Acad. Sci. U.S.A. 2004,
101, 11943–11948. (b) Barrero, A. F.; del Moral, J. F Q.; Sa´nchez,
E. M.; Arteaga, J. F. Eur. J. Org. Chem. 2006, 1627–1641. (c) Koh,
J. H.; Mascarenhas, C.; Gagne´, M. R. Tetrahedron 2004, 60, 7405–
7510. (d) Torre, M. C.; Sierra, M. A. Angew. Chem., Int. Ed. 2004,
43, 160–181.
(20) (a) Zhao, Y. J.; Chng, S. S.; Loh, T. P. J. Am. Chem. Soc. 2007, 129,
492–493. (b) Zhao, Y. J.; Loh, T. P. Chem. Commun. 2008, 1434–
1436. (c) Zhao, J. F.; Zhao, Y. J.; Loh, T. P. Chem. Commun. 2008,
1353–1355.
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A R T I C L E S
Zhao and Loh
Table 1. N-Acetal-TiCl4-Promoted Polyene Cyclization
Figure 1. Two possible pathways for mixed-acetal (N-acetal)-initiated
polyene cyclization.20,22,23
moderate diastereoselectivities (dr ) 66:18:16, 52% ee for
tricycle) (Scheme 3).20a In addition, acetal-initiated cyclization
products are very versatile and can be easily converted into
various optically active tricyclic terpene compounds (Scheme
5). Oxidation of the cyclization product 2 provided ketones 4
and 6. Hydrogenation of 2 afforded terpenoid 7 in 70% yield.
Since the chiral oxocarbenium generated from 1,3-dioxane
A was believed to be responsible for the good asymmetric
selectivity, we decided to carry out the study of mixed acetal
(N-acetal) with the hope of generating the chiral iminium
intermediate to obtain the aza-polycyclic compounds.
Previously, N-acetal-initiated polyene cyclizations have been
demonstrated by Speckamp,9 Kano,21 and Grieco,22 and the
iminium intermediate, which was preferentially formed, pro-
moted the intramolecular polyene cyclization successfully
(Scheme 6).9
a Isolated yield. b Monocyclized isomers were isolated together with
the desired tricylic products in a mixture of 74:26 (based on 1H NMR).
Table 2. N-Acetal-TiCl4-Promoted Polyene Cyclization with
Various Substrates
It is interesting to note that, by using N-acetal, the reaction can
proceed through two possible pathways (Figure 1), one through
the oxocarbenium20 and the other via the iminium22,23 intermediate.
Hence, in the case of intermolecular N-acetal-promoted polyene
cyclization, it is not clear whether iminium or oxocarbenium will
be the active species responsible for the cyclization.
Entry
R
Substrate
Producta
Yield (%)b 8 + 8′
drc (8:8′)
1
2
3
4
5
-
1
8 + 8′
62
51
50
62
50
89:11
89:11
93:7
90:10
88:12
4-Me
3-Me
2-Me
4-OMe
1a
1b
1c
1d
8a + 8a′
8b + 8b′
8c + 8c′
8d + 8d′
Our initial focus was to find proper N-acetal initiators to react
with polyene 1 (Table 1). Therefore, polyene 1 was subjected
to cyclization using various N-acetals in the presence of different
Lewis acids. No reaction occurred when 1 was treated with
mixed acetal B in the presence of SnCl4 (Table 1, entry 1). When
acyl substituent on the acetal was replaced by a tosyl group,
cyclization fortunately proceeded to afford the tricyclic product
8 in 30% yield together with 9% yield of the alcohol 5 (Table
1, entry 2). The best yield (62% yield) was obtained when TiCl4
was used instead of SnCl4 (Table 1, entry 3). On the other hand,
when N-acetal D was used, the cyclization product 9 was
isolated in 64% yield which was contaminated with monocy-
clized isomer (entry 4). In a summarizing note, the optimal
reaction condition was to use 2.0 equiv of TiCl4 and 2.0 equiv
of five-membered N-acetal C.
a Side-chain-cleaved products 5 were also isolated in 5-9% yield.
b Isolated yield. c The isomers of benzylic chiral center were observed.
The values of dr were determined based on 1H NMR integration of
benzylic CH.
Subsequently, we extended this method to the asymmetric
version of chiral N-acetal24-promoted polyene cyclization (Table
3). Various chiral N-acetals were subjected to the reaction with
polyene 1 under the optimized conditions. The results are shown
in Table 3. In all cases, good yields of cyclization products 5
were obtained. It was worthy to note that side-chain-cleaved
chloride product 10 was the only observed product. Stirring of
the chloride product 10 in silica gel in mixed wet solvent of
dichloromethane and hexane (1:1) for 24 h afforded the
corresponding alcohol 5/5′ in good yields. In addition, we found
that the chirality of oxygenated carbon in the chiral N-acetal is
important for the achievement of high diastereoselectivities.
Without a chiral environment on oxygenated carbon, no
selectivity was observed (Table 3, entry 1).
With the optimized reaction conditions in hand, cyclization
of various polyenes with different benzene ring analogues was
carried out and the results are summarized in Table 2. In all
cases, the products were obtained in moderate yields with good
diastereoselectivities.
(24) The chiral N-acetal was synthesized from optical pure 1,2-hydroxy
amine using the modified Didier’s procedure: (a) Didier, E.; Fouque,
E.; Taillepied, I.; Commercon, A. Tetrahedron Lett. 1994, 35, 2349–
2352. (b) Agami, C.; Couty, F.; Mathieu, H. Tetrahedron Lett. 1996,
37, 4001–4002. (c) Commercon, A.; Be´zarf., D.; Bernard, F.; Bourzat,
J. D. Tetrahedron Lett. 1992, 33, 5185–5188. (d) Hajji, C.; Zaballos-
Garc´ıa, E.; Sepu´lveda-Arques, J. Synth. Commun. 2003, 33, 4347–
4354. (e) Grieco, P. A.; Fobare, W. F. J. Chem. Soc., Chem. Commun.
1987, 185–186.
(21) (a) Kano, S.; Yokomatsu, T.; Yuasa, Y.; Shibuya, S. J. Org. Chem.
1985, 50, 3449–3453. (b) Kano, S.; Yokomastu, T.; Nemoto, H.;
Shibuya, S. J. Am. Chem. Soc. 1986, 108, 6746–6748.
(22) Grieco, P. A.; Fobare, W. F. J. Chem. Soc., Chem. Commun. 1987,
185–186.
(23) For reviews about N-acyliminium fromN-acetal initiated cyclization,
see: (a) Maryanoff, B. E.; Zhang, H. C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. ReV. 2004, 104, 1431–1628. (b) Marson,
C. M. ARKIVOC 2001, 1, 1–16.
(25) For structure detail of ketone 13, see Supporting Information.
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Bioinspired Polyene Cyclization
A R T I C L E S
Table 3. Screen for Different Chiral N-Acetals as Initiators
Table 4. N-Acetal-Promoted Asymmetric Polyene Cyclization
Using Various Substrates
Entry
R
Polyene
Producta
Yieldb (%)
dr
eec (%)
1
2
3
4
5
-
1
5 + 5′
54
56
55
58
41
93:7
93:7
92:8
91:9
90:10
71
62
60
60
71
4-Me
3-Me
2-Me
4-OMe
1a
1b
1c
1d
5a + 5a′
5b + 5b′
5c + 5c′
5d + 5d′
a Only structures of 5 are shown. b Isolated yield. c Alcohols were
oxidized into corresponding ketones 6 to remove benzylic chiral centers;
ee values were determined by chiral HPLC analysis of ketones 6.
Scheme 7
a Only the structure of 12 is shown. Diastereomeric ratio ) 93:7. Alcohols
were oxidized into corresponding ketone 1325 to remove benzylic chiral
centers; ee value was determined by chiral HPLC analysis of ketone 13.
Scheme 8
a The possible formation of the other enantiomer of 5′ cannot be
ruled out. b Isolated yield. c Alcohol was oxidized into ketone to destroy
benzylic chiral center; ee values were determined by HPLC analysis of
corresponding isolated pure ketone.
It is worthy to note that even tetracyclic terpenoid could be
obtained efficiently in good ee (62%) and moderate yield (40%)
(Scheme 7).
The products of N-acetal-promoted polyene cyclization were
very versatile and could be readily converted into diverse
terpenoid compounds (Scheme 8). Oxidation of alcohol 5
provided ketone 6 in 93% yield with 71% ee.
The best result we obtained was 54% yield and 71% ee when
N-acetal G was used as the initiator for the cyclization (Table
3, entry 3). When mesyl group was used instead of the tosyl
group (Table 3, entry 4), better ee (73%) was obtained but the
yield was lower (30%). Generally, other aromatic sulfonyl
groups also gave respectable yields and moderate enantiose-
lectivities. Surprisingly, the mesityl group diminished the
asymmetric induction of the polyene cyclization reaction (0%
ee, Table 3, entry 8).
Beckmann rearrangement protocol26 was applied to the ketone
6, and amide 15 was obtained in 50% yield with up to 96% ee
after a single recrystallization (Scheme 8). Alcohol 5 could be
converted to alkene 16, and upon ozonolysis, ketone 4 was
obtained in 62% ee and 25% yield over three steps. In addition,
(26) For review about Beckmann rearrangement, see: (a) Beckmann, E.
Ber. Dstch. Chem. Ges. 1886, 19, 998. (b) Gawley, R. E. Org. React.
John Wiley and Sons, Inc.: New York, 1988; Vol. 35, p 9. (c)
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Chapter 1.9, p 341.
Using this optimized conditions, we screened various polyene
substrates and the results are summarized in Table 4. In all cases,
the products were obtained in good yields and good ee.
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A R T I C L E S
Zhao and Loh
Figure 3. X-ray structure of 8, 50% probability was chosen for the ellipsoids.
Scheme 11
Figure 2. X-ray crystallography structures of 6 and 15, 50% probability
was chosen for the ellipsoids.
Scheme 9
only achiral N-acetal but also chiral N-acetal underwent oxo-
carbenium pathway to initiate polyene cyclization.
The following transition states (Figure 4) were proposed to
account for the observed stereochemistries. Initial step involved
the selective cleavage of the oxazolidine ring of N-acetal G to
afford an active oxocarbenium intermediate. The active oxo-
carbenium intermediate was subsequently attacked from the less
hindered Re face by the polyene 1 via antiperiplanar, open-
chain transition states (paths a and b).27 The favored path b
was proposed to be much less sterically demanding and lower
in energy compared to path a, thereby affording the major
enantiomer of 6. Cyclization through unfavorable path a
provided the minor enantiomer of 6.
Scheme 10
Conclusion
In summary, we have developed an asymmetric Lewis acid
mediated intermolecular acetal or N-acetal-initiated cationic
polyene cyclization to form tricyclic and tetracyclic terpenoids.
Diverse optically active terpenoids were readily synthesized in
few steps via simple modification sequences. In addition, an
oxocarbenium intermediate was found to be responsible for the
good asymmetric selectivity for this type of reaction. Optimiza-
tions of this chiral N-acetal-TiCl4 system are in progress in order
to achieve higher enantioselectivities.
acid-promoted elimination of brominated 5 provided benzylic
carbocation, which underwent proton shift to afford alkene 18.
Moreover, intermolecular trapping of benzylic carbocation
afforded amide 17.
The absolute stereochemistry of polyene cyclization adducts 6
([R]21 ) +36.5, 71% ee) promoted by chiral N-acetal was
D
determined by comparison of its optical rotation with that of ketone
6 ([R]21D ) +16.2, 52% ee) (obtained from chiral acetal-promoted
polyene cyclization).21 The stereochemistry of 6 was further verified
by X-ray crystallography (Figure 2) and chiral HPLC analyses.
Experimental Section
General procedure for preparation of chiral N-acetal: To a 50 mL
round-bottom flask with a magnetic stirring bar were added aminoin-
danol (0.745 g, 5.0 mmol, 1.0 equiv), THF (20 mL), and water (20
mL). Triethyl amine (1.01 g, 10.0 mmol, 2.0 equiv) was then added
via syringe. The solution was cooled to 0 °C prior to addition of TsCl
(0.953 g, 5.0 mmol, 1.0 equiv). The reaction mixture was allowed to
proceed at room temperature for another 12 h before quenching with
ice water (30 mL). The aqueous layer was extracted with ethyl acetate
(2 × 40 mL), and the combined organic extracts were washed with
water (30 mL) and brine (30 mL) and dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo. The residual crude product
was purified by column chromatography to afford the desired product
Discussion
While these new findings showed encouraging results, the
actual cyclization mechanism was found to be different from
previously reported N-acetal-promoted polyene cyclization
reactions. Instead of an iminium intermediate, an oxocarbenium
intermediate was most likely generated when N-acetal was
exposed to TiCl4 (Path a, Scheme 9).
Such a conclusion was based on the following findings:
(1) In the case of racemic studies using N-acetal C, we
observed only the oxocarbenium type product 8 without
detection of iminium type product (Scheme 10 and Figure 3).
(2) In the case of chiral N-acetal E derived from primary
alcohol, we isolated 53% asymmetric cyclization product 19 as
O-benzyl ether without side chain cleavage in the presence of
TiCl4 (1.0 equiv) (Scheme 11). These results suggested that not
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10028 J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008

Bioinspired Polyene Cyclization
A R T I C L E S
Figure 4. Proposed mechanism for N-acetal-promoted polyene cyclization.
as a white solid. The white solid was then placed in a 50 mL dry
round-bottom flask with a magnetic stirring bar. ClCH2CH2Cl (30 mL)
and PhCH(OMe)2 (1.52 g, 10.0 mmol, 2.0 equiv) were added via
syringe. The reaction mixture was stirred at room temperature, and
camphorsulfonic acid (CSA) (116 mg, 0.5 mmol, 0.1 equiv) was added
in one portion. The reaction mixture was heated at 70 °C for 12 h
before quenching with NaHCO3 (50 mL) at room temperature. The
aqueous layer was extracted with CH2Cl2 (2 × 40 mL). The combined
organic extracts were washed with water (30 mL) and brine (30 mL)
and dried over anhydrous sodium sulfate, filtered, and concentrated
in vacuo. The residual crude product was purified by column
chromatography to afford the desired product as a white solid: mp
151-153 °C; 90% yield over two steps; [R]20D ) +35.7 (c ) 2.64,
1.11 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.6, 146.1, 135.0,
128.8, 128.0, 126.5, 125.6, 125.3, 125.2, 124.5, 72.1, 55.5, 51.9,
38.4, 38.0, 37.3, 30.9, 30.0, 24.8, 19.4, 18.7, 16.1; HRMS (EI) m/z
calcd for C24H30O [M]+ 334.2297, found 334.2293; FTIR (KBr) ν
3342, 2966, 2914, 1487, 1448, 1377, 1215, 1051, 756, 700 cm-1
.
General procedure for oxidation of cyclization product 5 to
ketone 6: To an oven-dried 25 mL round-bottom flask equipped
with a magnetic stirring bar were added PCC (0.129 g, 0.6 mmol,
12.0 equiv), 4 Å molecular sieve (0.3 g, oven-dried over 48 h),
silica gel (0.3 g, oven-dried over 48 h), and CH2Cl2 (10 mL). The
mixture was cooled to 0 °C, and alcohol 5 (19 mg, 0.05 mmol, 1.0
equiv) in CH2Cl2 (1 mL) was added dropwise. The reaction was
gradually warmed to room temperature and was stirred for another
12 h. The mixture was filtered through a pad of silica gel and flushed
with 200 mL of CH2Cl2. The solution was concentrated in vacuo.
The residual crude product was purified by flash column chroma-
tography to afford the ketone 6 as a colorless solid: mp 73-75 °C;
1
CHCl3); Rf 0.50 (hexane/ethyl acetate ) 4:1); H NMR (400 MHz,
CDCl3) δ 7.75-7.72 (m, 2H), 7.44-7.37 (m, 1H), 7.31-7.25 (m, 2H),
7.18-7.10 (m, 2H), 7.10-6.97 (m, 6H), 6.05 (s, 1H), 5.38 (d, J )
5.50 Hz, 1H), 4.41 (td, J ) 5.26, 0.73 Hz, 1H), 3.03 (d, J ) 17.16
Hz, 1H), 2.95 (dd, J ) 17.42, 4.83 Hz, 1H), 2.40 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 144.3, 140.0, 139.7, 138.4, 135.0, 129.9, 128.7,
128.5, 128.0, 127.9, 126.9, 126.2, 125.1, 93.3, 81.9, 67.8, 37.4, 21.6;
HRMS (EI) m/z calcd for C23H21NO3S [M]+ 391.1242, found
391.1243; FTIR (NaCl) ν 3421, 1579, 1458, 1423, 1350, 1288, 1165
yield 93%, ee 71%; [R]21 ) +36.9 (c ) 0.98, CHCl3); Rf 0.70
D
(hexane/ethyl acetate ) 4:1); 1H NMR (400 MHz, CDCl3) δ
8.0-7.97 (m, 1H), 7.54-7.45 (m, 2H), 7.27-7.09 (m, 6H), 3.42
(dd, J ) 12.56, 2.45 Hz, 1H), 2.99 (dd, J ) 17.17, 6.11 Hz, 1H),
2.88 (ddd, J ) 17.50, 11.07, 7.01 Hz, 1H), 2.45 (dt, J ) 13.04,
2.97 Hz, 1H), 2.40-2.15 (m, 1H), 1.93 (dd, J ) 13.71, 6.27 Hz,
1H), 1.92-1.50 (m, 4H), 1.29 (s, 3H), 1.06 (s, 3H), 0.95 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 204.3, 149.4, 139.1, 134.9, 132.7,
129.0, 128.5, 128.2, 125.8, 125.4, 124.5, 54.3, 52.2, 38.5, 38.0,
37.0, 31.4, 30.7, 25.2, 23.3, 18.5, 18.2; HRMS (EI) m/z calcd for
C24H28O [M]+ 332.2140, found 332.2134; FTIR (KBr) ν 3070,
2868, 1670, 1653, 1629, 1377, 1288, 1120, 1001, 873, 759, 723
cm-1
.
General procedure for N-acetal-TiCl4-promoted asymmetric
polyenel cyclization reactions: To a 10 mL round-bottom flask with
a magnetic stirring bar were added N-acetal G (78 mg, 0.2 mmol,
2.0 equiv) and CH2Cl2 (1.5 mL) at room temperature. The solution
was cooled to -78 °C prior to addition of TiCl4 (1.0 M in CH2Cl2,
0.2 mL, 2.0 equiv). CH2Cl2 (0.5 mL) solution of polyene 1 (23
mg, 0.1 mmol, 1.0 equiv) was added via syringe. The reaction was
stirred at -78 °C for 1 h before quenching with saturated NaHCO3
aqueous solution (5 mL). The mixture was gradually warmed to
room temperature and was stirred for another 0.5 h. The aqueous
layer was extracted with CH2Cl2 (3 × 20 mL), and the combined
organic layers were washed with water (20 mL) and brine (20 mL),
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
To the residual crude product in a 25 mL round-bottom flask were
added silica gel (10 g), hexane (10 mL), CH2Cl2 (10 mL), and water
(1 mL). The mixture was stirred for 24 h at room temperature. The
mixture was then purified by flash column chromatography. Alcohol
5 was obtained in 54% yield as a colorless oil: [R]21D ) +14.7 (c
) 4.0, CHCl3); Rf 0.75 (hexane/ethyl acetate ) 4:1); 1H NMR (400
MHz, CDCl3) δ 7.01-7.38 (m, 9H), 5.21 (d, J ) 3.87 Hz, 1H),
2.97 (ddd, J ) 17.42, 6.62, 1.74 Hz, 1H), 2.83 (ddd, J ) 17.42,
11.50, 6.96 Hz, 1H), 2.30 (dt, J ) 12.54, 3.14 Hz, 1H), 2.01-1.91
(m, 1H), 1.87 (dd, J ) 13.45, 2.94 Hz, 1H), 1.84-1.70 (m, 2H),
1.66-1.58 (m, 1H), 1.43-1.26 (m, 2H), 1.25 (s, 3H), 1.24 (s, 3H),
cm-1
.
Acknowledgment. This paper is dedicated to Professor Elias
J. Corey (Harvard University) on the occasion of his 80th birthday.
We thank Dr. Yong-Xin Li (Nanyang Technological University)
for X-ray analyses. We gratefully acknowledge the Nanyang
Technological University and the Singapore Ministry of Education
Academic Research Fund Tier 2 (No. T206B1221) for the financial
support of this research.
Supporting Information Available: Experimental procedures,
spectroscopic data for new compounds, chiral HPLC traces of
4, 6, 6a-6d, 13, and 15 and cif files for E, G, H, 6, 8, and 15.
This material is available free of charge via the Internet at http://
pubs.acs.org.
JA802896N
9
J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008 10029